Overview
| Uniprot ID | P19525 |
|---|
| Protein Name | Interferon-induced, double-stranded RNA-activated protein kinase |
|---|
| Gene Name | EIF2AK2 |
|---|
| Organism | Homo sapiens |
|---|
Kla Sites from experimental identification
| Position |
Flanking peptide |
| 444 |
TSLKNDGKRTRSKGT |
Function
IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection (PubMed:18835251, PubMed:19189853, PubMed:19507191, PubMed:21072047, PubMed:21123651, PubMed:22381929, PubMed:22948139, PubMed:23229543). Inhibits viral replication via the integrated stress response (ISR): EIF2S1/eIF-2-alpha phosphorylation in response to viral infection converts EIF2S1/eIF-2-alpha in a global protein synthesis inhibitor, resulting to a shutdown of cellular and viral protein synthesis, while concomitantly initiating the preferential translation of ISR-specific mRNAs, such as the transcriptional activator ATF4 (PubMed:19189853, PubMed:21123651, PubMed:22948139, PubMed:23229543). Exerts its antiviral activity on a wide range of DNA and RNA viruses including hepatitis C virus (HCV), hepatitis B virus (HBV), measles virus (MV) and herpes simplex virus 1 (HHV-1) (PubMed:11836380, PubMed:19189853, PubMed:19840259, PubMed:20171114, PubMed:21710204, PubMed:23115276, PubMed:23399035). Also involved in the regulation of signal transduction, apoptosis, cell proliferation and differentiation: phosphorylates other substrates including p53/TP53, PPP2R5A, DHX9, ILF3, IRS1 and the HHV-1 viral protein US11 (PubMed:11836380, PubMed:19229320, PubMed:22214662). In addition to serine/threonine-protein kinase activity, also has tyrosine-protein kinase activity and phosphorylates CDK1 at 'Tyr-4' upon DNA damage, facilitating its ubiquitination and proteasomal degradation (PubMed:20395957). Either as an adapter protein and/or via its kinase activity, can regulate various signaling pathways (p38 MAP kinase, NF-kappa-B and insulin signaling pathways) and transcription factors (JUN, STAT1, STAT3, IRF1, ATF3) involved in the expression of genes encoding pro-inflammatory cytokines and IFNs (PubMed:22948139, PubMed:23084476, PubMed:23372823). Activates the NF-kappa-B pathway via interaction with IKBKB and TRAF family of proteins and activates the p38 MAP kinase pathway via interaction with MAP2K6 (PubMed:10848580, PubMed:15121867, PubMed:15229216). Can act as both a positive and negative regulator of the insulin signaling pathway (ISP) (PubMed:20685959). Negatively regulates ISP by inducing the inhibitory phosphorylation of insulin receptor substrate 1 (IRS1) at 'Ser-312' and positively regulates ISP via phosphorylation of PPP2R5A which activates FOXO1, which in turn up-regulates the expression of insulin receptor substrate 2 (IRS2) (PubMed:20685959). Can regulate NLRP3 inflammasome assembly and the activation of NLRP3, NLRP1, AIM2 and NLRC4 inflammasomes (PubMed:22801494). Plays a role in the regulation of the cytoskeleton by binding to gelsolin (GSN), sequestering the protein in an inactive conformation away from actin (By similarity)
Protein Sequence
10
MAGDLSAGFF
20
MEELNTYRQK
30
QGVVLKYQEL
40
PNSGPPHDRR
50
FTFQVIIDGR
60
EFPEGEGRSK
70
KEAKNAAAKL
80
AVEILNKEKK
90
AVSPLLLTTT
100
NSSEGLSMGN
110
YIGLINRIAQ
120
KKRLTVNYEQ
130
CASGVHGPEG
140
FHYKCKMGQK
150
EYSIGTGSTK
160
QEAKQLAAKL
170
AYLQILSEET
180
SVKSDYLSSG
190
SFATTCESQS
200
NSLVTSTLAS
210
ESSSEGDFSA
220
DTSEINSNSD
230
SLNSSSLLMN
240
GLRNNQRKAK
250
RSLAPRFDLP
260
DMKETKYTVD
270
KRFGMDFKEI
280
ELIGSGGFGQ
290
VFKAKHRIDG
300
KTYVIKRVKY
310
NNEKAEREVK
320
ALAKLDHVNI
330
VHYNGCWDGF
340
DYDPETSDDS
350
LESSDYDPEN
360
SKNSSRSKTK
370
CLFIQMEFCD
380
KGTLEQWIEK
390
RRGEKLDKVL
400
ALELFEQITK
410
GVDYIHSKKL
420
IHRDLKPSNI
430
FLVDTKQVKI
440
GDFGLVTSLK
450
NDGKRTRSKG
460
TLRYMSPEQI
470
SSQDYGKEVD
480
LYALGLILAE
490
LLHVCDTAFE
500
TSKFFTDLRD
510
GIISDIFDKK
520
EKTLLQKLLS
530
KKPEDRPNTS
540
EILRTLTVWK
550
KSPEKNERHT
C
Gene Ontology
| Classification |
GO ID |
Description |
| Cellular Component |
GO:0005737 |
cytoplasm |
| Biological Process |
GO:0043410 |
positive regulation of MAPK cascade |
| Biological Process |
GO:1901224 |
positive regulation of non-canonical NF-kappaB signal transduction |
| Biological Process |
GO:0032874 |
positive regulation of stress-activated MAPK cascade |
| Biological Process |
GO:1901532 |
regulation of hematopoietic progenitor cell differentiation |
| Biological Process |
GO:1902036 |
regulation of hematopoietic stem cell differentiation |
| Biological Process |
GO:1902033 |
regulation of hematopoietic stem cell proliferation |
| Biological Process |
GO:1900225 |
regulation of NLRP3 inflammasome complex assembly |
| Biological Process |
GO:0006446 |
regulation of translational initiation |
| Biological Process |
GO:0035455 |
response to interferon-alpha |
| Biological Process |
GO:0009615 |
response to virus |
| Cellular Component |
GO:0005829 |
cytosol |
| Cellular Component |
GO:0016020 |
membrane |
| Cellular Component |
GO:0005654 |
nucleoplasm |
| Cellular Component |
GO:0005634 |
nucleus |
| Cellular Component |
GO:0048471 |
perinuclear region of cytoplasm |
| Cellular Component |
GO:0005840 |
ribosome |
| Molecular Function |
GO:0005524 |
ATP binding |
| Molecular Function |
GO:0003725 |
double-stranded RNA binding |
| Molecular Function |
GO:0004694 |
eukaryotic translation initiation factor 2alpha kinase activity |
| Molecular Function |
GO:0042802 |
identical protein binding |
| Molecular Function |
GO:0016301 |
kinase activity |
| Molecular Function |
GO:0004715 |
non-membrane spanning protein tyrosine kinase activity |
| Molecular Function |
GO:0004672 |
protein kinase activity |
| Molecular Function |
GO:0019888 |
protein phosphatase regulator activity |
| Molecular Function |
GO:0106310 |
protein serine kinase activity |
| Molecular Function |
GO:0004674 |
protein serine/threonine kinase activity |
| Molecular Function |
GO:0003723 |
RNA binding |
| Biological Process |
GO:0140374 |
antiviral innate immune response |
| Biological Process |
GO:0034198 |
cellular response to amino acid starvation |
| Biological Process |
GO:0051607 |
defense response to virus |
| Biological Process |
GO:0006351 |
DNA-templated transcription |
| Biological Process |
GO:0008285 |
negative regulation of cell population proliferation |
| Biological Process |
GO:2000766 |
negative regulation of cytoplasmic translation |
| Biological Process |
GO:0033689 |
negative regulation of osteoblast proliferation |
| Biological Process |
GO:0017148 |
negative regulation of translation |
| Biological Process |
GO:0045071 |
negative regulation of viral genome replication |
| Biological Process |
GO:0043123 |
positive regulation of canonical NF-kappaB signal transduction |
| Biological Process |
GO:0032722 |
positive regulation of chemokine production |
| Biological Process |
GO:0001819 |
positive regulation of cytokine production |
Reference
PMID: N/A